Indolo-quinolizidine derivatives

ABSTRACT

New compounds of the formula ##STR1## are provided wherein R 1  is hydrogen, and R 2  stands for an alkyl group and optically active enanthiomers and pharmaceutically acceptable salts thereof.

This is a division of application Ser. No. 575,038, filed May 6, 1975.

This invention relates to new indolo-quinolizidine derivatives andpharmaceutical compositions containing the same, as well as to a processfor the preparation thereof.

More particularly the invention relates to new indolo-quinolizidinederivatives having the general formula (I) or salts or optically activeisomers of the same ##STR2## wherein R₁ stands for hydrogen or an acylgroup, and

R₂ stands for an alkyl group.

Those compounds of the general formula (I) wherein R₁ stands forhydrogen or an alkylcarbonyl group having optionally one or moresubstituents and R₂ stands for alkyl are particularly preferred.

The most preferred new compounds of the general formula (I) are thosewherein R₁ stands for hydrogen, lower alkylcarbonyl, or benzoyloptionally having one or more alkoxy substituent(s).

The new compounds of the general formula (I) as well as the salts andoptically active isomers thereof possess valuable pharmacologicalproperties and can be used primarily as vasodilatating agents.

Several 1-disubstituted-indolo-quinolizidines have been described in theliterature, some of which, such as vincamine and its derivatives,possess valuable pharmaceutical effects. The preparation of thesedisubstituted derivatives is described e.g. in J. Am. Chem. Soc. 87,1580 (1965) and Tetrahedron Letters 1973, 191.

These known methods are, however, unsuitable to introduce a substituentinto position 1 of the indo-quinolizidine ring wherein the methylenegroup attached to the ring carbon atoms is connected to the remainder ofthe side chain through an oxygen atom.

The compounds of the general formula (I) or the salts or opticallyactive isomers thereof are prepared according to the invention asfollows: a compound of the general formula (II) ##STR3## wherein R₂stands for alkyl, is reacted with formaldehyde, and, if desired, thethus-obtained compound of the general formula (I), wherein R₁ stands forhydrogen and R₂ stands for alkyl, or a salt thereof is acylated, and, ifdesired, a compound of the general formula (I), wherein R₁ stands foracyl and R₂ stands for alkyl, is subjected to hydrolysis, and/or, ifdesired, a racemic compound of the general formula (I) or a salt thereofis resolved, and/or, if desired, a free base of the general formula (I)is converted into its salts, and/or, if desired, a salt of a compound ofthe general formula (I) is converted into the free base.

In the above formulae R₂ represents preferably a C₁₋₄ alkyl group, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butylgroup.

The starting substances of the general formula (II) can be used eitherin the form of the free bases or as their salts, preferably as the acidaddition salts formed e.g. with hydrochloric acid, hydrobromic acid,perchloric acid, perbromic acid, etc. When a salt of a compound havingthe general formula (II) is used as starting substance, this salt isconverted into the free base prior to reacting it with formaldehyde. Forthis purpose preferably a base, e.g. a dilute aqueous solution of aninorganic base (such as an alkali hydroxide, e.g. sodium hydroxide,potassium hydroxide, etc.) can be used. The base can be used in a molarexcess of about 20 to 40%. The free base of the general formula (II) isliberated from its salts preferably in an inert, water-immiscibleorganic solvent. As solvent e.g. a halogenated hydrocarbon, such aschloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane,trichloroethylene, etc. can be used. The liberation of the base isperformed preferably in an inert atmosphere, such as in nitrogen orargon atmosphere. Since the reaction proceeds in a two-phase mixture, itis preferable to apply constant stirring. The base liberates within ashort time, generally after 5 to 20 minutes of stirring. The temperatureof this reaction may vary within wide limits, the reaction is carriedout, however, preferably at room temperature. When the reactionterminates the phases are separated from each other, the organic phaseis dried, and subsequently concentrated to about 10 to 30% of itsoriginal volume. As drying agent preferably potassium carbonate is used,other well-known drying agents, however, can also be applied.

Thereafter the concentrate obtained in the above step is admixed withformaldehyde. Formaldehyde is introduced preferably in the form ofparaformaldehyde. It is preferred to apply paraformaldehyde in a 1.5 to3 molar excess related to the amount of the compound of the generalformula (II). The reaction is performed at elevated temperatures, suchas at 100° to 250° C, preferably at 160° to 170° C. Under suchconditions the reaction proceeds generally within 3 to 5 hours,particularly within 4 hours.

In this reaction compounds of the general formula (I) containing ahydrogen atom as substituent R₁ are formed.

If a compound of the general formula (I) wherein R₁ stands for an acylgroup is to be prepared, a compound of the general formula (I) whereinR₁ is hydrogen is treated with an appropriate acylating agent.

Any acylating agent known in the organic chemistry can be used in thisreaction. The acylating agents suitable to acylate a hydroxy groupattached to an aliphatic chain are particularly preferable.

As acylating agent e.g. an optionally substituted aliphatic, aromatic orheteroaromatic carboxylic acid or the respective acid halides oranhydrides, furthermore an optionally substituted aliphatic, aromatic orheteroaromatic sulfonic acid or the respective acid halides can be used.The primary aliphatic carboxylic anhydrides, such as acetic anhydride,propionic anhydride, etc., furthermore the optionally substitutedaromatic carboxylic acids and the respective acid halides, such asbenzoic acid, trimethoxybenzoyl chloride, etc., proved to be veryadvantageous acylating agents.

The acylation is carried out under well-known reaction conditions.

The necessary amount of the acylating agent depends on the reactivity ofthe starting substances, and may vary e.g. within 1 to 10 moles, such aswithin 1 to 5 moles calculated for 1 mole of the starting substancehaving the general formula (I). When a liquid acylating agent is used ingreat excess, this acylating agent may serve simultaneously as a solventfor the reaction.

If desired, a catalyst, such as iodine can be added to the reactionmixture in order to accelerate or complete, respectively, the acylation.When a free acid is used as acylating agent, preferably a dehydratingagent, such as dicyclohexyl carbodiimide is added to the reactionmixture. One may also add an acid binding agent, e.g. a tertiary organicbase, such as pyridine, triethylamine, etc. to the mixture, particularlywhen an acid chloride or acid anhydride is used as acylating agent. Thetertiary organic base can also be added in excess, in this event thebase may serve simultaneously as a solvent for the reaction. It shouldbe noted, however, that the use of catalysts, dehydrating agents or acidbinding agents can be omitted when the components taking part in theacylation are sufficiently reactive per se.

The acylation is generally conducted in the presence of a solvent. Assolvent, e.g. an excess of the acylating agent (such as propionicanhydride) or the tertiary organic base (such as pyridine) can be used,but inert organic solvents, such as dimethyl formamide, etc. can beapplied as well.

The acylation is conducted under substantially anhydrous conditions. Forthis purpose dry chemicals, e.g. dry pyridine, dry dimethyl formamide,etc. should be used.

The temperature of the acylation may vary within wide limits dependingon the nature of the starting substances and the solvent. The reactiontemperature may range e.g. from 0° C up to the boiling point of thesolvent, it is preferable, however, to conduct the reaction between roomtemperature and 100° C.

The reaction time also may vary within wide limits depending on thereaction temperature and on the nature of the starting substances. Thereaction time may range e.g. from 10 minutes up to 6 days.

The reaction mixture obtained in the acylation step can be processedaccording to usual methods, e.g. by evaporating and alkalinating thereaction mixture, or by pouring the mixture onto ice, alkalinating thesystem, extracting the mixture and evaporating the extract, etc. Whenthe reaction mixture is evaporated and the concentrate is renderedalkaline the base of the general formula (I), wherein R₁ stands for acylgroup and R₂ stands for alkyl group, is generally obtained inwell-filterable, crystalline state. If necessary, the obtainedcrystalline substance can be recrystallized easily from an appropriatesolvent or solvent mixture. When the processing of the reaction mixtureyields an oily substance, this oily substance can be crystallizedgenerally very easily using conventional solvents, such as loweraliphatic alcohols, e.g. methanol.

If desired, the solid, powdery products can be purified byrecrystallization from an appropriate solvent or solvent mixture. Assolvents for recrystallization e.g. aliphatic alcohols, particularlylower aliphatic alcohols or their mixtures with water, such as methanol,aqueous methanol, etc. can be used.

The analysis data of the thus-obtained crystalline bases of the generalformula (I) are in good agreement with the calculated values. Thestructures of the obtained products can be confirmed further by IR andNMR spectroscopy.

Those compounds of the general formula (I) wherein R₁ stands for acylcan be hydrolyzed to yield the corresponding compounds of the generalformula (I) wherein R₁ is hydrogen. The hydrolysis is performedaccording to well-known methods, preferably using an acid or base ashydrolyzing agent.

The free bases of the general formula (I) can be converted into theiracid addition salts. For this purpose preferably pharmaceuticallyacceptable mineral or organic acids, such as hydrogen halides (e.g.hydrochloric acid, hydrobromic acid), phosphoricacid, organic carboxylicacids (e.g. acetic acid, propionic acid, glycolic acid, maleic acid,succinic acid, tartaric acid, citric acid, salicylic acid or benzoicacid), alkylsulfonic acids (e.g. methanesulfonic acid), arylsulfonicacids (e.g. p-toluenesulfonic acid) etc. can be used. In turn, the acidaddition salts can be treated with a base to yield the compounds of thegeneral formula (I) in the form of the free bases.

The compounds of the general formula (I) contain an asymmetric carbonatom, thus they may exist in the form of optically active isomers. Thesynthesis according to the invention yields the end-products in racemicform, which can be resolved into the individual optically active isomersby well-known methods. The resolution can be performed after any step ofthe synthesis, thus, for example, one may resolve a compound of thegeneral formula (I) wherein R₁ stands for hydrogen, and may use one ofthe thus-obtained optically active isomers in the subsequent acylationstep.

As mentioned above the compounds of the general formula (I) and theirpharmaceutically acceptable acid addition salts possess vasodilatatingproperties. The vasodilatating effects of the new compounds have beeninvestigated by the following pharmacological experiments.

The tests were carried out on narcotized dogs. The results prove thatthe compounds possess significant vasodilatating effects. The compoundsincrease primarily the blood flow of the limbs, but some of themeffectively increase the cerebral blood flow as well. In comparison withthe significant increase of the blood flow, the temporary fall in bloodpressure (lasting from about 1 to 2 minutes) and the increase of heartrate is relatively low.

The tests were performed on dogs narcotized with chloralose-urethane.The blood flow of the limbs was measured at the arteria femoralis,whereas the cerebral blood flow was investigated by measuring the flowof the arteria carotis interna. The circulation resistance wascalculated from the blood pressure and blood flow walues.

The compounds under examination were dissolved in a pH 4 ascorbic acidsolution, and vere administered in an intravenous dosage of 1 mg/kg. Theobserved changes were expressed as percentages in relation to thecontrols. 6 aminals were used in each of the individual tests. The datalisted in Table 1 are the mean values calculated for the individualgroups.

For comparison purposes the respective data of apovincaminic acid ethylester, the most active one of the compounds with related structures, arealso listed in the Table.

                  Table 1                                                         ______________________________________                                        Active agent                                                                           (1)     (2)     (3)   (4)   (5)   (6)                                ______________________________________                                        Apovinc-                                                                      aminic                                                                        acid ethyl                                                                             + 58    -35     + 16  -20   -28   +14                                ester                                                                         (A)      +183    -59.5   + 36  -37.5 -17.5 +16.5                              (B)      +237.5  -74.5   + 2   -13   -39   +13.5                              (C)      +234    -74     +113  -63.5 -36.5 +58.5                              ______________________________________                                         Notes:                                                                        (1) blood flow of the limbs                                                   (2) circulation resistance of the limb blood vessels                          (3) cerebral blood flow                                                       (4) circulation resistance of the cerebral blood vessels                      (5) blood pressure                                                            (6) heart rate                                                                (A) a compound of the general formula (I) wherein R.sub.2 is ethyl and        R.sub.1 is hydrogen                                                           (B) a compound of the general formula (I) wherein R.sub.2 is ethyl and        R.sub.1 is acetyl                                                             (C) a compound of the general formula (I) wherein R.sub.2 is ethyl and        R.sub.1 is propionyl                                                     

As it appears from the data of the above Table the new compoundsaccording to the invention are about four times as active as thereference substance with respect to the increase of the blood flow inthe limbs, whereas their activities exceed more than three times that ofthe reference substance with respect to the increase of the cerebralblood flow.

The effective intravenous or oral dosage of the new compounds may varywithin about 0.1 to 2 mg./kg. body weight. It should be noted, however,that the actual dosage is always determined in accordance with the needsof the patient, thus in some instances dosages lower or higher thanthose mentioned above are to be applied.

The compounds of the general formula (I) or the pharmaceuticallyacceptable acid addition salts thereof can be converted intopharmaceutical compositions suitable for enteral or parenteraladministration. These compositions may contain the new compoundsaccording to the invention either alone or in combination with otherbiologically active substances. When preparing the pharmaceuticalcompositions the active agent(s) is(are) admixed with conventionalinert, non-toxic, pharmaceutically acceptable carriers and/or diluents.As carrier e.g. water, gelatine, lactose, starch, magnesium stearate,talc, vegetable oils, gum arabic, polyalkylene glycols, vaseline, etc.can be used. The compositions may optionally contain conventionalpharmaceutical auxiliary agents, such as preservatives, salts foradjusting the osmotic pressure, buffers, flavouring agents, etc. Thepharmaceutical compositions can be prepared in conventional forms, e.g.as solid formulations (tablets, coated tablets, capsules, etc.) or asliquid preparations (e.g. solutions, suspensions, emulsions, etc.) Theobtained compositions can be sterilized or subjected to other finishingoperations, if necessary.

The invention is elucidated in detail by the aid of the followingnon-limiting Examples.

EXAMPLE 11-Hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin

10.0 g. (28.5 moles) of1-ethyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine perchlorate aredissolved in 100 ml. of dichloromethane, and 75 ml. of distilled waterand 20 ml. of a 2N sodium hydroxide solution are added to thedichloromethane solution in argon atmosphere under constant stirring.The reaction mixture is stirred for 10 minutes, thereafter the organicphase is separated, dried over anhydrous potassium carbonate, andfiltered. The filtrate is concentrated in vacuo, under argon atmosphere,to a final volume of 15 ml., and 2.0 g. (66.8 mmoles) ofparaformaldehyde are added to the concentrate. The solvent is evaporatedin vacuo, and the residue is heated at 160°-170° C (bath temperature)for 4 hours in a closed vessel.

The obtained glassy substance is dissolved in hot methanol and thesolution is allowed to cool, whereupon white crystals start to separate.The mixture is kept in refrigerator, thereafter the crystals arefiltered off and washed with methanol. 4.15 g. of the title compound areobtained, m.p.: 232°-234° C. This substance is recrystallized fromtenfold volume of methanol to yield 3.45 g. (42.7%) of the purifiedproduct: m.p.: 235°-236° C.

Analysis: Calculated for C₁₈ H₂₄ N₂ O (M = 284.39): C: 76.02%; H: 8.51%;N: 9.85%; Found: C: 76.16%; H: 8.61%; N: 10.18%.

IR-spectrum (in KBr-pellets): 3380 (ind-NH), 3140 - 2980 (--OH) cm⁻¹.

NMR-spectrum (DMSO-d₆) : τ = 0.7 (1H, ind =NH), 2.60-3.20 (4H, aromaticprotons), 4.33 (1H, --OH), 6.52 (1H in the anellation position).

EXAMPLE 21-Acetoxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine

2.50 g. (8.82 mmoles) of1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizineare dissolved in 15 ml. of absolute pyridine. 15 ml. of acetic anhydrideare added to the solution, and the mixture is allowed to stand at roomtemperature for three days. Thereafter the solution is evaporated invacuo, and the oily residue is stirred with a 5% sodium hydrocarbonatesolution. The separated solid substance is filtered off, washed withwater, dried, and recrystallized first from aqueous methanol and thenfrom methanol. 1.75 g. (61.2%) of the title compound are obtained in theform of shiny crystals melting at 96°-97° C.

Analysis: Calculated for C₂₀ H₂₆ N₂ O₂ (M = 326.42): C: 73.59%; H:8.03%; N:8.58%; Found: C: 73.59%; H: 8.06%; N: 8.66%.

IR-spectrum (in KBr pellet): 3370 (ind =NH), 1720 (=C=O) cm⁻¹.

NMR-spectrum (DMSO-d₆): τ = 1.38 (1H, indol =NH), 2.40 - 3.02 (4H,aromatic protons), 5.62 (2H, CH₃ --CO--CH₂ --), 6.51 (1H, in theanellation position), 7.76 (3H, CH₃ --CO--).

EXAMPLE 31-Propionyloxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine

0.50 g. of iodine are dissolved in 100 ml. of propionic anhydride, and3.0 g. (10.5 mmoles) of1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizineare added in small portions to the red solution. The reaction mixture isimmersed into a 50° C water bath for 15 minutes, then it is allowed tostand at room temperature for 16 hours.

The acidic solution is poured onto ice, the mixture is alkalinated with40% sodium hydroxide solution (pH: 10 to 11), and extracted with 50 ml.,30 ml. and 20 ml. of dichloroethane. The organic extracts are combined,dried over magnesium sulfate, filtered, and the filtrate is evaporatedin vacuo. The oily residue is crytallized from methanol. 2.10 g. (59.1%)of the title compound are obtained in the form of white crystals meltingat 107°-108° C.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₂ (M = 340.45): C: 74.08%; H:8.29%; N: 8.23%; Found: C: 74.14%; H: 8.44%; N: 8.12%.

IR-spectrum (in KBr-pellet): 3390 (ind. =NH), 1718 (=C=O) cm⁻¹.

EXAMPLE 41-Benzoyloxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine

2.0 g. (7.02 mmoles) of1-hydroxymethyl-1ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizineand 2.0 g. (16.4 mmoles) of benzoic acid are dissolved in 20 ml. ofabsolute dimethyl formamide, and a solution of 4.0 g. (19.5 mmoles) ofdicyclohexyl carbodiimide in 15 ml. of absolute dimethyl formamide isadded. The solution is allowed to stand at room temperature for twodays, the separated solids are filtered off, and 1.0 g. (8.2 mmoles) ofbenzoic acid and 2.0 g. (9.7 mmoles) of dicyclohexyl carbodiimide areadded to the filtrate. The filtrate is allowed to stand at roomtemperature for additional three days. The separated solids are filteredoff, and the filtrate is evaporated in vacuo. The oily residue isstirred with a 5% sodium hydrocarbonate solution, the separatedcrystalline substance is filtered off, dried, and recrystallized firstfrom aqueous methanol and then from methanol.

2.65 g. (97.1%) of the title compound are obtained as crystals meltingat 148°-149° C.

Analysis: Calculated for C₂₂ H₂₈ N₂ O₂ (M = 340.47): C: 77.29%; H:7.27%; N: 7.21%; Found: C: 77.19%; H: 7.01%; N: 7.39%.

IR-spectrum (in KBr pellet): 3290 (ind.=NH), 1710 (=C=O) cm⁻¹.

EXAMPLE 51-(3,4,5-Trimethoxybenzoylmethyl)-1-ethyl-1,2,3,4,6,,7,12,12b-octahydro-indolo[2,3-a]quinolizine

1.30 g. (4.58 mmoles) of1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizineand 2.30 g. (10 mmoles) of 3,4,5-trimethoxybenzoyl chloride aredissolved in 15 ml. of absolute pyridine, and the solution is heated ona steam bath for 10 hours under a reflux condenser. The solution isevaporated in vacuo, and the oily residue is stirred first with a 5%sodium hydrocarbonate solution and then with distilled water. Theseparated solids are filtered off, dried, and recrystallized frommethanol.

2.05 g. (93.5%) of the title compound are obtained as white crystalsmelting at 170°-171° C.

Analysis: Calculated for C₂₈ H₃₄ N₂ O₅ (M = 478.57): C: 70.27%; H:7.16%; N: 5.85%; Found: C: 70.08%; H: 7.09%; N: 5.61%.

IR-spectrum (in KBr pellet): 3381 (ind.=NH), 1698 (=C=O) cm⁻¹.

EXAMPLE 61-Hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine

1.50 g. (4.6 mmoles) of1-acetoxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizineare dissolved in 15 ml. of methanol, and a solution of 0.40 g. (10mmoles) of sodium hydroxide in 4 ml. of distilled water is added. Themixture is refluxed for 45 minutes, then diluted with 30 ml. ofdistilled water. The separated crystals are filtered off and washed withdistilled water. 1.05 g. of the title compound are obtained; m.o.:230°-233° C.

After recrystallization from methanol 0.95 g. (72.8%) of purifiedproduct are obtained; m.p.: 234°-236° C.

The analytical and spectral data of the obtained product are identicalwith those described in Example 1.

What we claim is:
 1. A compound of the formula (I), ##STR4## wherein R₁stands for hydrogen, and R₂ stands for an alkyl group having 1 to 4carbon atoms, the optically active enanthiomers and the pharmaceuticallyacceptable salts thereof. 2.1-Hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine.